Arthritic Disease
One of the most intensively studied arthritic diseases is rheumatoid arthritis. There is a major genetic contribution for the predisposition to rheumatoid arthritis. People who inherit a group of defined HLA major histocompatibility complexes account for 90% of the rheumatoid arthritis patients (Winchester, R., Adv. Immunol. 56:389-466, 1994). Rheumatoid arthritis is a chronic and destructive disease that primarily affects the joints of the extremities and is characterized by inflammation of the synovium and destruction of joint structural components. The symptoms and morphology suggest a local immune response. Both cell-mediated and humoral immune responses may contribute to development of lesions (Abbas, et al., Cellular and Molecular Immunology, Ch. 20, W. B. Saunders Co., Philadelphia, 1990).
Numerous cytokines have been detected in the synovial (joint) fluid of arthritic patients, and these cytokines are believed to activate resident synovial cells to produce hydrolytic enzymes (e.g., collagenase and matrix metalloproteinase) that mediate the destruction of the cartilage.
The etiology of rheumatoid arthritis is unknown. It is likely that many different causes trigger the development of what is diagnosed as rheumatoid arthritis. There are bacterial infections which are known to result in the development of arthritis. These would include arthritis which results from infections with Borrelia, Yersinia, Salmonella, Shigella, Campylobacter or Chlamydia species. Regardless of the cause, once the joint becomes inflamed there is a well documented immune mediated attack on one of the major structural components of the joints, collagen (Trentham, D. E., et al., J. Exp. Med. 146:857-868, 1977).
There are several experimental animal models of arthritis. Collagen injections in mice, rats and primates result in the development of arthritis. The best studied animal model is collagen-induced arthritis in DBA/1 mice. Arthritic disease can also be induced in mice infected with Borrelia burgdorferi, the causative agent of Lyme arthritis.
Current treatment regimes for rheumatoid arthritis include symptomatic drugs in combination with disease-modifying drugs (Machold, K. P., et al., Annals Rheum. Dis. 51:1039-1043, 1992). Disease modifying drugs include gold salts, D-Penicillamine, hydroxychloroquine, and cytostatic drugs which have limited efficacy and significant toxicity. Arthritic diseases caused by infectious agents, such as Borrelia burgdorferi, are treated with symptomatic drugs in combination with antimicrobial therapy (Steere, A. C., N. Engl. J. Med., 321:586-596, 1989). Regardless of the cause, symptomatic treatment of arthritis is uniformly steroid therapy.
Arthritic disease can also be caused by infectious agents such as Borrelia burgdorferi, which causes Lyme disease. Current methods of treating Lyme arthritis include symptomatic drugs in combination with antimicrobial therapy to eradicate the spirochete.
1,25(OH).sub.2 D.sub.3 and Analogs
The 1.alpha.-hydroxylated metabolites of vitamin D-most importantly 1.alpha.,25-dihydroxyvitamin D.sub.3 and 1.alpha.,25-dihydroxyvitamin D.sub.2 --are known as highly potent regulators of calcium homeostasis in animals and humans. More recently, their activity in cellular differentiation has also been established. As a consequence, many structural analogs of these metabolites, such as compounds with different side-chain structures, different hydroxylation patterns, or different stereochemistry, have been prepared and tested. Important examples of such analogs are 1.alpha.-hydroxyvitamin D.sub.3, 1.alpha.-hydroxyvitamin D.sub.2, various side-chain fluorinated derivatives of 1.alpha.,25-dihydroxyvitamin D.sub.3, and side-chain homologated analogs. Several of these known compounds exhibit highly potent activity in vivo or in vitro, and possess advantageous activity profiles and thus are in use, or have been proposed for use, in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, multiple sclerosis, and certain malignancies.
1,25-Dihydroxyvitamin D.sub.3 As An Immunomodulator
The first indication that vitamin D might modulate immunity was the discovery that peripheral blood monocytes and activated T lymphocytes have 1,25-dihydroxyvitamin D.sub.3 receptors (reviewed in Manolagas, S. C., et al. Mol. and Cell. Endocrin. 43:113-122, 1985). Despite many investigations, 1,25-dihydroxyvitamin D.sub.3 immunomodulatory activity remains largely undefined and often controversial (reviewed in Manolagas, S. C., et al., supra, 1985; Rigby, W. F. C., Today 9:54-57, 1988; and Lemire, J. M., et al., J. Nutr. 125:1704S-1708S, 1995).
The action of 1,25-dihydroxyvitamin D.sub.3 on human peripheral blood mononuclear cells (PBMC) has been studied extensively in vitro. These in vitro experiments showed that the hormone inhibited mitogen-stimulated proliferation of the PBMC (Lemire, J. M., et al., J. Clin Invest. 74:657-661, 1984; Rigby, W. F. C., et al., J. Clin. Invest. 74:1451-1455, 1984) by reducing IL-2 production (Lemire, J. M., et al., J. Immunol. 134:3032, 1985; Iho, S., et al., Immunol. Let. 11:331-336, 1985; Manolagas, S. C., et al., J. Clin. Endocrinol. Met. 63:394, 1986) at the level of gene transcription (Alroy, I., et al., Mol. Cell. Biol. 15:5789-5799, 1995). In contrast, Bhalla, et al. (Bhalla, A. K., et al., J. Immunol. 133:1748-54, 1984) reported that the hormone did not inhibit mitogen-stimulated mouse spleen and thymus cell proliferation, although it did inhibit antigen-stimulated proliferation of these cells. Lacey, et al. (Lacey, D. L., et al., J. Immunol. 138:1680-1686, 1987) reported that the hormone actually stimulated mitogen-induced proliferation of cloned mouse T-cells. No studies have directly addressed the action of the hormone on T lymphocyte differentiation and function in vivo.
Disparate results have been reported for T lymphocyte IFN-.gamma. synthesis in vitro. Rigby, et al. (Rigby, W. F. C., et al., J. Clin. Invest. 79:1659-1664, 1987) and Reichel, et al. (Reichel, H., et al., Proc. Natl. Acad. Sci. USA 84:3387-3389, 1987) showed that 1,25-dihydroxyvitamin D.sub.3 decreased IFN-.gamma. synthesis in mitogen-stimulated PBMC. However, Muller, et al. (Muller, K., et al. Immunol. Let. 35:177-182, 1993) reported that the hormone had no effect on IFN-.gamma. synthesis in human T-cell lines. The hormone inhibited cytotoxic T lymphocyte development but not cytotoxic function (Merino, F., et al., Cell. Immunol. 118:328-336, 1989).
There is controversy about 1,25-dihydroxyvitamin D.sub.3 action on monocyte/macrophage cells in vitro. 1,25-Dihydroxyvitamin D.sub.3 enhanced a myeloid leukemia cell's differentiation to the macrophage phenotype (Manolagas, S. C., et al., supra, 1985). It also increased monocyte/macrophage production of M-CSF, TNF-.alpha., and prostaglandin E2, but decreased IL-12 synthesis (Lemire, J. M., et al., FASEB J. 8:A745 (abs), 1994). The hormone decreased macrophage costimulatory function for T-cell proliferation (Rigby, W. F. C. and M. G. Waugh, Arthritis Rheum. 35:110-119, 1992). Disparate results have been reported for 1,25-dihydroxyvitamin D.sub.3 effects on IL-1 synthesis in vitro. The hormone decreased IL-1 synthesis in some reports (Iho, S., et al., supra, 1985; Tsoukas, C. S., et al., J. Clin. Endocrinol. Metab. 69:127-133, 1989) and increased IL-1 synthesis in other reports (Amento, E. P., J. Clin. Invest. 73:731-739, 1987; Bhalla, A. K., et al., Immunol. 72:61-64, 1991; Fagan, D. L., et al., Mol. Endocrinol. 5:179-186, 1991). Likewise, some investigators reported that 1,25-dihydroxyvitamin D.sub.3 enhanced class II protein expression in vitro (Morel, P. A., et al., J. Immunol. 136:2181-2186, 1986) but others reported that it decreased class II protein expression (Amento, E. P., supra, 1987; Carrington, M. N., et al., J. Immunol. 140:4013-4018, 1988; Rigby, W. F. C., et al., Blood 76:189-197, 1990). Together these findings provide no clear and consistent view of how 1,25-dihydroxyvitamin D.sub.3 might modify macrophage function. No studies have directly addressed the action of the hormone on monocyte/macrophage differentiation and function in vivo.
There is also controversy about 1,25-dihydroxyvitamin D.sub.3 action on B lymphocytes (reviewed in Rigby, W. F. C., supra, 1988). Lemire, et al. (Lemire, J. M., et al., supra, 1984) reported that the hormone inhibited mitogen-stimulated I.sub.g G and I.sub.g M synthesis by human peripheral blood mononuclear cells. Suppressive and enhancing effects of 1,25-dihydroxyvitamin D.sub.3 on mitogen-stimulated B cell proliferation and on antibody synthesis in vitro have been shown. In vivo, 1,25-dihydroxyvitamin D.sub.3 has been reported to enhance antibody synthesis in some studies (Abe, J., et al., Endocrinology 124:2645-2647, 1989; Ross, T. K., et al., Vitamins Hormones 49:281-326, 1994; Daynes, R. A., et al., Infec. Immun. 64:1100-1109, 1996) and to inhibit it in other studies (Lemire, J. M., et al., supra, 1995).
There is a great deal of interest in arthritis treatments. Present drug treatments for arthritis include non-steroidal anti-inflammatory drugs (see Paulus, H. E. and D. E. Furst, Arthritis and Allied Conditions in A Textbook of Rheumatology, D. J. McCarty, Ed., Lea & Febiger, Philadelphia, Pa., pp. 507-543, 1989) such as naproxen, piroxicam, indomethacin, sulindac, aspirin, salicylsalicyclic acid, sodium meclofenamate, diflunisal, tolmetin, phenylbutazone, oxyphenbutazone, ibuprofen, fenoprofen, ketoprofen; disease-modifying antirheumatic drugs such as chloroquine, hydroxychloroquine, D-penicillamine, auranofin, aurothiomalate, methotrexate, azathioprine, sulphasalazine; and steroidal anti-inflammatory drugs such as corticosteroids (see McCarty, D. J., Arthritis and Allied Conditions. A Textbook of Rheumatology, Lea & Febiger, Philadelphia, Pa., pp. 659-782, 905-990, 1989).
The American College of Rheumatology and the International League Against Rheumatism published a core set of rheumatoid arthritis outcome measures to be used in clinical trials (Felson, D. T., et al., Arthritis Rheumatol. 36:729-740, 1993). These outcome measures include:
1. Progression in physical parameters such as number of joints that are painful, number of joints that are swollen, and both patient and physician global opinion of rheumatoid arthritis activity. PA0 2. An assessment of joint physical function like angle of joint deformity, limited joint motion, and decreased functional capacity as described by Young, et al. (Young, A. M., et al. Br. J. Rheumatol. 27:94-101, 1988) and McCarty, et al. (supra, 1989) and measured with the Health Assessment Questionnaire (Felson, D. T., et al., supra, 1993). PA0 3. Pain PA0 4. Laboratory measures of the inflammatory acute phase reaction like C-reactive protein as described by van PA0 5. Radiographic progression in serial radiographs taken over .ltoreq.1 year of the wrists, hands, and feet, scored as described by Sharp (Sharp, J. T., Scoring radiographic abnormalities in rheumatoid arthritis. In: Radiologic Clinics of North America 34(2):233-241, 1996), Wilhelm, et al. (Wilhelm, F. E., et al., Arthritis Rheum. 37(suppl.):S336, 1994), Nance, et al. (Nance, E. P., et al., Invest. Radiol. 21:922-927, 1986), or some similarly quantitative method.
Leeuwen, et al. (van Leeuwen, M., et al. Arthritis Rheum. 37(suppl. 9):S331, 1994).
Improvement has been defined (Felson, D. T., et al., supra, 1993) as a .ltoreq.20% improvement in painful/tender joint counts and in swollen joint counts, and .ltoreq.20% improvement in at least three of the other criteria (patient opinion, physician opinion, physical function, pain index, or acute phase reactant).
A new drug category, disease-controlling antirheumatic therapy (D-CART), was recently defined (Edmonds, J. P., J. Rheumatol. 21(suppl.41):1-63, 1994). To qualify for D-CART status, a therapy must produce a sustained improvement in physical function, a decrease in inflammatory synovitis, and a slowing or halting of progressive structural joint damage as documented by serial radiographs or other imaging studies.
Needed in the art is an improved arthritis treatment method.